Stage-dependent associations of Cardiovascular-Kidney-Metabolic Syndrome with Cognitive Decline, Depression, and Neuroimaging Signatures in multi-regional older adults

Background Cardiovascular-Kidney-Metabolic (CKM) syndrome is a multisystem condition associated with adverse outcomes, yet its impact on age-related cognitive health remains understudied. We examined associations of CKM with neurocognitive and neuropsychiatric outcomes, modifiable physical and psychosocial factors contributing to cognitive impairment across CKM stages, and neuroimaging correlates. Methods Global aging cohorts (mean follow-up 6.5 years) and the Cohort Studies of Memory in an International Consortium (5.4 years) were used. CKM stages (0-4) were defined according to AHA framework. Longitudinal domain-specific cognitive changes were assessed using linear mixed-effects models, and depressive symptoms using generalized linear regression with individual participant data approach. Population-attributable fractions were estimated for six modifiable factors associated with cognitive impairment across CKM stages. Cross-sectional associations with 34 neuroimaging biomarkers were examined in UK Biobank. Results Among 28,242 participants, advanced CKM stages (3-4) were associated with accelerated cognitive decline, particularly in attention, executive function, and language. Associations were stronger in younger individuals, men, and those with less education, but not modified by APOE 4 status. Advanced CKM stages were associated with depressive symptoms among cognitively unimpaired individuals. Modifiable factors accounted for 24.8% of cognitive impairment risk across CKM stages, mainly social isolation (7.0%), depressive symptoms (5.2%), and physical inactivity (5.2%). Advanced CKM stages were linked to widespread MRI alterations (27 biomarkers), especially white matter hyperintensity. Conclusion Advanced CKM stages are associated with accelerated cognitive decline and greater cerebrovascular burden. Addressing psychosocial factors and physical inactivity, alongside management of CKM risk factors, may help reduce cognitive impairment.